The use of metal complexes in medicine can be traced back to 3500 BC and due to its particular physical and chemical properties gold has always been one of the many metals in use1,2 Despite its wide use most of the gold based drugs have not been designed specifically for their function, and their mode of action is often unknown2 The use of gold(0) is limited and is mostly used as a non-irritating food decoration and additive′ Most of the gold-based drugs employ gold(I) and gold(III).1 
The use of gold(I) based drugs has until recently been the main focus of medicinal research.3,4 Their usefulness has mostly been in the treatment of rheumatoid arthritis, but testing against different cancer cell lines has been reported.3 Gold(I) is a soft d10 metal ion. The most common coordination geometry for gold(I) complexes is linear, with the molecules usually consisting of a central gold(I) ion coordinated by either phosphorous or sulfur donor ligands.4,5 Au(I) complexes undergo facile ligand exchange in aqueous solutions, with the rate of ligand exchange increasing in the order R3P<RS−<X−. The lability of the ligands contributes to both the therapeutic activity of Au(I) antiarthritic compounds and the side effects observed with these drugs.4 One of the most well known of the gold(I) drugs is Auranofin (FIG. 1) which is widely used in the treatment of rheumatoid arthritis.
Auranofin and its many derivatives have also become the focus of research into gold(I) based anti-cancer agents. Several complexes have been found to exhibit cytotoxicity greater than that of cisplatin against melanoma and leukemia cancer cell lines in particular.5 The in vitro test results of many gold(I) chelates against various human cancer cell lines have been promising.4,5 
However, many of these complexes have never entered into clinical trials, since they have been associated with cardiotoxicity in preclinical trials.2 Due to this cardiotoxicity of gold(I) chelates, gold(III) has become the focus of research into gold based chemotherapeutic agents.5,6 
One of the first metal based drugs that was used in the treatment of cancer was cisplatin.6,7 Cisplatin is still widely used today in the treatment of several types of tumors, particularly testicular cancer. Its use is, however, hindered by some clinical problems such as a severe toxicity towards non-cancerous tissue and the frequent occurrence of initial and acquired resistance to the treatment.6 The most concerning adverse side effect is nephrotoxicity correlated to platinum binding and inactivation of renal thiol-containing enzymes.6 These drawbacks to the success of cisplatin in anticancer chemotherapy has raised great interest in the study of metal complexes to be used as antitumor agents, instigating the ongoing investigation of alternative metal-based drugs. The allure of gold(III) as an anti-tumor agent is that it has a d8 electron configuration, with vacant d(x2-y2) orbitals, and therefore adopts a rigorously square planar coordination geometry. Gold(III) is therefore isostructural and isoelectronic to platinum(II).8 Despite the similarity to platinum(II) literature relating to the use of gold(III) as a chemotherapeutic agent is scarce.6 The rarity of data on gold(III) complexes probably derives from their high redox potential and relatively poor stability, which make their use rather problematic under physiological conditions.5,6 The gold(III) ion can be readily reduced to the more stable gold(I) ion or even metallic gold(0) under the in vivo reducing conditions, characteristic of the mammalian environment.5 The coordination of a ligand, which is a strong σ-donor and π-acceptor ligand that can stabilize the gold(III) ion under physiological conditions is therefore critical if gold(III) is to be used in the treatment of cancer.5,9

There are currently no commercially available gold(III) compounds being used as chemotherapeutic agents. There are, however, many gold(III) complexes that have shown very promising in vitro and in vivo activity against many different human cancer cell lines.10 The structures of a range of gold(III) chelates, which have Au—N bonds, that have been tested for cytotoxicity are shown in Scheme 2.
The two pyridyl gold(III) species, [AuCl3(Hpm)] and [AuCl2(pm)] (Scheme 2) have good cytotoxicity towards a range of human cancer cell lines, particularly human ovarian cancer cell lines. The results of these tests although promising were comparable to the screening results of NaAuCl4 which is their parent compound.10 The other drawback of these compounds is that although stable in organic solutions, they are susceptible to reduction in aqueous buffer media, which limits their practical usefulness.10,11 The bipyridine type complexes, [Au(bipy)(OH)2][PF6] and [Au(bipy-H)(OH)][PF6] were, on the other hand, found to be stable in aqueous buffer media. Unfortunately they were found to interact with calf thymus DNA only weakly. Despite this weak interaction with calf thymus DNA, both bipyridyl gold(III) complexes show IC50 values falling into the micromolar range against an ovarian carcinoma cell line. [Au(bipy-H)(OH)][PF6] is the most active of the two compounds. The results of the tests against other ovarian cancer cell lines as well as leukemia cell lines were less encouraging.9 
The gold(III) complexes with multidentate N-donor ligands; [Au(phen)Cl2]Cl, [Au(terpy)Cl]Cl2, [AuCl(dien)]Cl2, [Au(cyclam)](ClO4)2Cl and [Au(en)2]Cl2, showed reasonable stability in physiological buffer solutions at 37° C. These gold(III) complexes have been greatly stabilized by the chelation of the gold(III) ion to polyamine ligands. This stabilization was evidenced by measurements of the reduction potentials of the complexes.8,10 The stabilization was less evident for the less basic phenanthrene and terpyridine ligands.8 With the exception of the complex [Au(cyclam)](ClO4)2Cl, all complexes exhibited good cytotoxicity against the human ovarian cancer cell line A2780. These complexes also exhibited good cytotoxicity towards the cisplatin-resistant A2780 ovarian cancer cell line; this suggests that gold(III) compounds might overcome the phenomenon of drug resistance.8,10 The free ligands that were coordinated to a gold(III) ion to give the complexes were also screened against the same cancer cell lines to ensure that the cytotoxicity was a result of the presence of the gold(III) ion. These test results showed that the free ethylenediamine ligand was devoid of any activity. The potency of free phenanthrene and terpyridine, on the other hand, was comparable to that of the respective gold(III) complexes making the screening results of these chelates difficult to interpret. The study did, however, prove that the cytotoxicity of [Au(en)2]Cl2 was a direct consequence of the presence of the gold(III) ion.10 
The complex [Au(azpy)Cl2]Cl, which contains a bidentate N-donor ligand, exhibited promising cytotoxic activity in cisplatin-sensitive and cisplatin-resistant ovarian carcinoma and leukemia cancer cell lines. Interestingly, solutions of [Au(azpy)Cl2]Cl underwent a cyclization reaction under physiological conditions leading to the formation of a tricyclic cationic organic compound, which also exhibited good cytotoxic activity.10,12 
The gold(III) dithiocarbamate complexes, are examples of gold(III) chelates with Au—S bond which are bound to ligands through a sulfur atom. Examples of dithiocarbamate complexes that have been screened against various cancer cell lines are shown below in Scheme 3.

The Gold(III) dithiocarbamate complexes that have been screened against various human cancer cell lines exhibited greater cytotoxic effects compared to cisplatin. The complexes were also bioactive against drug resistant cancer cell lines and induced apoptosis.6,7 The compounds have proven to be stabile under physiological conditions and readily bind to calf thymus DNA, inhibiting both DNA and RNA synthesis. Experiments on red blood cells indicated that haemolytic properties might contribute significantly to the bioactivity of the agents. The complexes triggered cancer cell death via apoptotic and non-apoptotic pathways and affected mitochondrial functions.6,7,10 The free ligand ESDT (Scheme 3) did not exhibit proteosome inhibitory activity and the parent gold salts KAuCl4 and KAuBr4 also showed weaker inhibitory activities than (ESDT)AuBr2.
Although the in vitro anti-cancer activity of gold(III) compounds has been documented for more than three decades, very few demonstrate promising in vivo anti-cancer activities. Among the gold(III) compounds in the literature that have undergone in vivo testing are the gold(III) dithiocarbamate compounds, which inhibited approximately 50% growth of breast cancer cells a month after the first dose of the compound.13 